Being precise with anticoagulation to reduce adverse drug reactions: are we there yet?

Anticoagulants are potent therapeutics widely used in medical and surgical settings, and the amount spent on anticoagulation is rising. Although warfarin remains a widely prescribed oral anticoagulant, prescriptions of direct oral anticoagulants (DOACs) have increased rapidly. Heparin-based parenteral anticoagulants include both unfractionated and low molecular weight heparins (LMWHs). In clinical practice, anticoagulants are generally well tolerated, although interindividual variability in response is apparent. This variability in anticoagulant response can lead to serious incident thrombosis, haemorrhage and off-target adverse reactions such as heparin-induced thrombocytopaenia (HIT). This review seeks to highlight the genetic, environmental and clinical factors associated with variability in anticoagulant response, and review the current evidence base for tailoring the drug, dose, and/or monitoring decisions to identified patient subgroups to improve anticoagulant safety. Areas that would benefit from further research are also identified. Validated variants in VKORC1, CYP2C9 and CYP4F2 constitute biomarkers for differential warfarin response and genotype-informed warfarin dosing has been shown to reduce adverse clinical events. Polymorphisms in CES1 appear relevant to dabigatran exposure but the genetic studies focusing on clinical outcomes such as bleeding are sparse. The influence of body weight on LMWH response merits further attention, as does the relationship between anti-Xa levels and clinical outcomes. Ultimately, safe and effective anticoagulation requires both a deeper parsing of factors contributing to variable response, and further prospective studies to determine optimal therapeutic strategies in identified higher risk subgroups

Warfarin dosing algorithms: A systematic review

AIMS:Numerous algorithms have been developed to guide warfarin dosing and improve clinical outcomes. We reviewed the algorithms available for various populations and the covariates, performances and risk of bias of these algorithms. METHODS:We systematically searched MEDLINE until 20 May 2020 and selected studies describing the development, external validation, or clinical utility of a multivariable warfarin dosing algorithm. Two investigators conducted data extraction and quality assessment. RESULTS:Of 10,035 screened records, 266 articles were included in the review, describing the development of 433 dosing algorithms, 481 external validations and 52 clinical utility assessments. Most developed algorithms were for dose-initiation (86%), developed by multiple linear regression (65%) and mostly applicable to Asians (49%) or Whites (43%). The most common demographic/clinical/environmental covariates were age (included in 401 algorithms), concomitant medications (270 algorithms) and weight (229 algorithms) while CYP2C9 (329 algorithms), VKORC1 (319 algorithms) and CYP4F2 (92 algorithms) variants were the most common genetic covariates. Only 26% and 7% algorithms were externally validated and evaluated for clinical utility, respectively, with less than 2% of algorithm developments and external validations being rated as having a low risk of bias. CONCLUSION:Most warfarin dosing algorithms have been developed in Asians and Whites and may not be applicable to under-served populations. Few algorithms have been externally validated, assessed for clinical utility, and/or have a low risk of bias which makes them unreliable for clinical use. Algorithm development and assessment should follow current methodological recommendations to improve reliability and applicability, and under-represented populations should be prioritized

A phase 1/2 study of the oral FLT3 inhibitor pexidartinib in relapsed/refractory FLT3-ITD-mutant acute myeloid leukemia.

FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitors (TKIs) have activity in acute myeloid leukemia (AML) patients with FLT3 internal tandem duplication (ITD) mutations, but efficacy is limited by resistance-conferring kinase domain mutations. This phase 1/2 study evaluated the safety, tolerability, and efficacy of the oral FLT3 inhibitor PLX3397 (pexidartinib), which has activity against the FLT3 TKI-resistant F691L gatekeeper mutation in relapsed/refractory FLT3-ITD-mutant AML. Ninety patients were treated: 34 in dose escalation (part 1) and 56 in dose expansion (part 2). Doses of 800 to 5000 mg per day in divided doses were tested. No maximally tolerated dose was reached. Plasma inhibitory assay demonstrated that patients dosed with ≥3000 mg had sufficient levels of active drug in their trough plasma samples to achieve 95% inhibition of FLT3 phosphorylation in an FLT3-ITD AML cell line. Based on a plateau in drug exposure, the 3000-mg dose was chosen as the recommended phase 2 dose. The most frequently reported treatment-emergent adverse events were diarrhea (50%), fatigue (47%), and nausea (46%). Based on modified response criteria, the overall response rate to pexidartinib among all patients was 21%. Twenty-three percent of patients treated at ≥2000 mg responded. The overall composite complete response rate for the study was 11%. Six patients were successfully bridged to transplantation. Median overall survival (OS) of patients treated in dose expansion was 112 days (90% confidence interval [CI], 77-150 days), and median OS of responders with complete remission with or without recovery of blood counts was 265 days (90% CI, 170-422 days). This trial was registered at www.clinicaltrials.gov as #NCT01349049

Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients

ObjectiveTo characterize, among European and Han Chinese populations, the genetic predictors ofmaculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepilepticdrugs.MethodsWe conducted a case-control genome-wide association study of autosomal genotypes, in-cluding Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent.Results from each cohort were meta-analyzed.ResultsWe report an association between a rare variant in the complement factor H–related 4(CFHR4) gene and phenytoin-induced MPE in Europeans (p= 4.5 × 10–11; odds ratio [95%confidence interval] 7 [3.2–16]). This variant is in complete linkage disequilibrium witha missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our resultsreinforce the association betweenHLA-A*31:01and carbamazepine hypersensitivity. We didnot identify significant genetic associations with MPE among Han Chinese patients.ConclusionsThe identification of genetic predictors of MPE in CFHR4 and CFH, members of thecomplement factor H–related protein family, suggest a new link between regulation of thecomplement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients

Prácticas docentes para creatividad en la universidad: estudio en Portugal y Brasil

Creativity is nowadays seen as an essential feature in higher education. Nevertheless, there is a discrepancy between the need for creativity and what higher education classrooms provide. This study assessed the perceptions of 1599 higher education students from two countries (1059 Brazilian and 540 Portuguese students), from two academic domains (Sciences and Technologies – Sc&T; Social Sciences, Arts, and Humanities – SScA&H), about the presence of creativity in their teachers’ instruction and evaluation practices. The study’s findings evidence interactive effects between the variables country and academic domain for most of the assessed factors: encouragement of new ideas, climate for the expression of ideas, and interest in students’ learning. Brazilian Sc&T students presented more negative perceptions of their classroom environments when compared to SScA&H students; Portuguese students showed opposite patterns of results. Some hypothetical explanations are discussed and future directions for research are presented.Criatividade é atualmente tomada como aspecto essencial na Educação Superior. Há, contudo, discrepância entre a necessidade de criatividade e o que a universidade proporciona. Este estudo avaliou percepções de 1599 alunos universitários de dois países (1059 brasileiros e 540 portugueses), de duas áreas curriculares (Ciências e Tecnologias – Sc&T; Ciências Sociais, Artes e Humanidades – SscA&H) sobre a presença de criatividade nas práticas docentes, instrucionais e avaliativas, de que são alvo. Os resultados mostraram efeitos interativos significativos entre as variáveis país e área curricular para a maioria dos fatores avaliados: encorajamento de novas ideias, clima para expressão de ideias e interesse pela aprendizagem dos alunos. Os estudantes brasileiros de Sc&T mostraram percepções mais negativas da sala de aula, comparados com os de SScA&H; os alunos portugueses obtiveram padrões opostos nos resultados. Algumas hipóteses explicativas são discutidas e são apresentadas orientações para pesquisa futura.La creatividad está actualmente considerada como aspecto esencial en la Educación Superior. Sin embargo, existe discrepancia entre la necesidad de creatividad y lo que la universidad ofrece. Este estudio evaluó percepciones de 1.599 estudiantes universitarios (1.059 de Brasil y 540 de Portugal) de dos áreas curriculares (Ciencia y Tecnología – Sc&T; Ciencias Sociales, Artes y Humanidades – SscA&T) acerca de la presencia de creatividad en las prácticas docentes, instructivas y evaluativas dirigidas a ellos. Los resultados mostraron efectos de interacción significativos entre las variables país y área curricular para la mayoría de los factores evaluados: fomento de nuevas ideas, entorno para la expresión de ideas e interés en el aprendizaje del estudiante. Los estudiantes brasileños de Sc&T mostraron percepciones más negativas de la clase en comparación con los de SSCA&H; los estudiantes portugueses obtuvieron patrones opuestos en los resultados. Algunas hipótesis explicativas se discuten y se presentan directrices para investigación futura.Thermo Scientificinfo:eu-repo/semantics/publishedVersio

Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients

Objective To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. Methods We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. Results We report an association between a rare variant in the complement factor H–related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 × 10–11; odds ratio [95% confidence interval] 7 [3.2–16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients. Conclusions The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H–related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients

Radically open-dialectical behavior therapy for adult anorexia nervosa: feasibility and outcomes from an inpatient program

Background Anorexia Nervosa (AN) is a highly life-threatening disorder that is extremely difficult to treat. There is evidence that family-based therapies are effective for adolescent AN, but no treatment has been proven to be clearly effective for adult AN. The methodological challenges associated with studying the disorder have resulted in recommendations that new treatments undergo preliminary testing prior to being evaluated in a randomized clinical trial. The aim of this study was to provide preliminary evidence on the effectiveness of a treatment program based on a novel adaptation of Dialectical Behavior Therapy (DBT) for adult Anorexia Nervosa (Radically Open-DBT; RO-DBT) that conceptualizes AN as a disorder of overcontrol. Methods Forty-seven individuals diagnosed with Anorexia Nervosa-restrictive type (AN-R; mean admission body mass index = 14.43) received the adapted DBT inpatient program (mean length of treatment = 21.7 weeks). Results Seventy-two percent completed the treatment program demonstrating substantial increases in body mass index (BMI; mean change in BMI = 3.57) corresponding to a large effect size (d = 1.91). Thirty-five percent of treatment completers were in full remission, and an additional 55% were in partial remission resulting in an overall response rate of 90%. These same individuals demonstrated significant and large improvements in eating-disorder related psychopathology symptoms (d = 1.17), eating disorder-related quality of life (d = 1.03), and reductions in psychological distress (d = 1.34). Conclusions RO-DBT was associated with significant improvements in weight gain, reductions in eating disorder symptoms, decreases in eating-disorder related psychopathology and increases in eating disorder-related quality of life in a severely underweight sample. These findings provide preliminary support for RO-DBT in treating AN-R suggesting the importance of further evaluation examining long-term outcomes using randomized controlled trial methodology

A multi-factorial analysis of response to warfarin in a UK prospective cohort

Background Warfarin is the most widely used oral anticoagulant worldwide, but it has a narrow therapeutic index which necessitates constant monitoring of anticoagulation response. Previous genome-wide studies have focused on identifying factors explaining variance in stable dose, but have not explored the initial patient response to warfarin, and a wider range of clinical and biochemical factors affecting both initial and stable dosing with warfarin. Methods A prospective cohort of 711 patients starting warfarin was followed up for 6 months with analyses focusing on both non-genetic and genetic factors. The outcome measures used were mean weekly warfarin dose (MWD), stable mean weekly dose (SMWD) and international normalised ratio (INR) > 4 during the first week. Samples were genotyped on the Illumina Human610-Quad chip. Statistical analyses were performed using Plink and R. Results VKORC1 and CYP2C9 were the major genetic determinants of warfarin MWD and SMWD, with CYP4F2 having a smaller effect. Age, height, weight, cigarette smoking and interacting medications accounted for less than 20 % of the variance. Our multifactorial analysis explained 57.89 % and 56.97 % of the variation for MWD and SMWD, respectively. Genotypes for VKORC1 and CYP2C9*3, age, height and weight, as well as other clinical factors such as alcohol consumption, loading dose and concomitant drugs were important for the initial INR response to warfarin. In a small subset of patients for whom data were available, levels of the coagulation factors VII and IX (highly correlated) also played a role. Conclusion Our multifactorial analysis in a prospectively recruited cohort has shown that multiple factors, genetic and clinical, are important in determining the response to warfarin. VKORC1 and CYP2C9 genetic polymorphisms are the most important determinants of warfarin dosing, and it is highly unlikely that other common variants of clinical importance influencing warfarin dosage will be found. Both VKORC1 and CYP2C9*3 are important determinants of the initial INR response to warfarin. Other novel variants, which did not reach genome-wide significance, were identified for the different outcome measures, but need replication

Genetic factors influencing warfarin dose in Black-African patients: a systematic review and meta-analysis.

Warfarin is the most commonly used oral anticoagulant in sub-Saharan Africa. Dosing is challenging due to a narrow therapeutic index and high inter-individual variability in dose requirements. To evaluate the genetic factors affecting warfarin dosing in Black-Africans, we performed a meta-analysis of 48 studies (2,336 patients). Significant predictors for CYP2C9 and stable dose included rs1799853 (CYP2C9*2), rs1057910 (CYP2C9*3), rs28371686 (CYP2C9*5), rs9332131 (CYP2C9*6), and rs28371685 (CYP2C9*11) reducing dose by 6.8, 12.5, 13.4, 8.1, and 5.3 mg/week respectively. VKORC1 variants rs9923231 (-1639G>A), rs9934438 (1173C>T), rs2359612 (2255C>T), rs8050894 (1542G>C), and rs2884737 (497T>G) decreased dose by 18.1, 21.6, 17.3, 11.7, and 19.6 mg/week, respectively while rs7294 (3730G>A) increased dose by 6.9 mg/week. Finally, rs12777823 (CYP2C gene cluster) was associated with a dose reduction of 12.7 mg/week. Few studies were conducted in Africa, and patient numbers were small, highlighting the need for further work in Black Africans to evaluate genetic factors determining warfarin response